Glioma remains the most frequent brain tumours in adults. The malignant form of glioma, grade IV also referred to as glioblastoma multiforme (GBM) is notoriously hard to treat. It returns in most cases despite virtually all current therapies, which include surgery, radiation and chemotherapy. Survival rates are very low, for example 14.6 months on average even when combining chemotherapy with radiation. No environmental risk factors have been identified and little is known about the biological mechanisms involved in the initiation and progression phases of these brain tumours.
In 1930, Otto Warburg proposed that cancer originates when a nonneoplastic cell adopts an anaerobic metabolism after two successive phases: (1) an irreversible injury of respiration and (2) the successful replacement of the irretrievably lost of respiration by glycolysis. According to this theory, the majority of cancer cells are believed to preferentially produce energy by producing lactacte from glucose under aerobic conditions, phenomenon commonly named “aerobic glycolysis” and referred as the Warburg's effect. Therefore, developing cancer treatment targeting this aerobic glycolysis metabolism pathway, which would allow the remodeling of the metabolism process towards an active respiration and production of energy by the mitochondria has raised interest in the last decade.
Some publications suggest the mitochondria of glioma cells to be a potential target for cancer chemotherapy (Daley et al., 2005, Biochemical and Biophysical Research Communications, 328 (2):623-632; Pilkington et al., 2008, Seminars in cancer biology England, 18 (3):226-235). These publications disclose a treatment, which involves clomipramine or in general tricyclics agents as inhibitors of the mitochondrial complex III and potential chemotherapy for glioma cells (cancer cells), without further radiotherapy or surgery. Said inhibitors induce apoptosis mediated by the activation of the mitochondrial route i.e. via the release of cytochrome C and activation of caspase-3. This kind of therapy would be possible because glioma cells (cancer cells) have a different metabolism than the normal cells.
WO 2008/031171 (Griffith University) also discloses some anti-cancer compounds and methods for treating or preventing cancer. In particular, pro-oxidant anti-cancer compounds are disclosed, such as pro-oxidant forms of vitamin E, which selectively interact with complex II (succinate-ubiquinone oxidoreductase) of the mitochondrial respiratory chain of cancerous cells, generate reactive oxygen species and induce apoptosis of those cells.
However, this therapeutic strategy makes the assumption that the biology and metabolism of every single cancer cell (such as glioma cells) is similar and unfortunately did not provide a significant progress in the treatment of glioma.
Although the exact cellular origin of gliomas remains unclear it is proposed that only a fraction of cancer cells with stem cell properties, usually named cancer stem cells (CSC), has true tumorigenic potential and constitutes a discrete reservoir of cancer initiating cells in glioma. The recent identification of Stem-like Cells (SC) in a number of human cancers like acute myeloid leukemias (AML), breast, ovarian and brain tumours has renewed interest in the hypothesis that cancers may arise from somatic mutations in adult stem/progenitor cells.
Brain tumour cancer initiating cells, know as Glioma-initiating cells (GICs) were initially identified as CD133+ cells but recent studies demonstrate a relative lack of specificity of this marker. These cells are heterogeneous populations of cells with different tumorigenic capacity, some tumour cells having a superior tumour initiating and propagating ability. Glioma-initiating cells (GICs) are responsible for the initiation and recurrence of gliomas. The role of glioma-initiating cells with stem cell properties has not yet been well investigated. These cells display characteristic stem cell features including self renewal capacity at single cell level, multipotency with evidence of astroglial, neuronal and oligodendroglial differentiation in vitro and tumorigenicity in vivo. As other human cancers, gliomas contain cellular hierarchies on the top of which tumour initiating and propagating cells with stem cell properties (called cancer stem cells-CSC) seem to control tumour growth. This minor population of cancer stem-like cells, GICs account only for about 5% of tumour cells (gliomas), may represent the source of tumour cell expansion, recurrence and metastasis, thus determining the biological behaviour of tumours including proliferation, progression, and subsequently response to therapy.
Targeting glioma-initiating cells remains challenging due to their rarity, instability in culture and the absence of robust tracer agents. So far, no efficient treatment against glioma-initiating cells has shown a complete eradication of the glioma growth or absence of recurrence in any of the orthotopic xenograft and/or transgenic mouse model. The resistance of glioma-derived tumour-initiating cells to conventional radiotherapy has been demonstrated (Bao et al., 2006; Clement et al., 2007). For example it is known that glioma-initiating cells are resistant to chemotherapeutic agents like temozolomide. These data might explain the inevitable recurrence of gliomas and define glioma-initiating cells as novel targets to overcome the resistance to conventional therapy in this disease.
For the moment no efficient treatment against recurrence of glioma is currently available. There is still a need to find an efficient treatment specifically directed to glioma-initiating cells. However, before identifying any efficient molecule against glioma-initiating cells and obtaining any significant improvement in glioma therapy, it is essential to better and deeper understand the cellular and molecular mechanisms of glioma-initiating cells.